Effects on FDA Morale and the Potential for en masse Resignations of that Agency’s Reviewers

In a previous blog we identified several critical processes that could be affected if there were major changes in the laws underpinning FDA review and approval of new drugs, biological therapies and vaccines.

Should Congress make major modifications in the Food, Drug and Cosmetics and Public Health Service Acts, the requirement for substantial evidence of both efficacy and safety could be altered. The resulting shift in assessment of risk/benefit could have a profound effect on the organization, procedures, internal guidance, workload, and approach of Agency Reviewers.

Over the last several years these Reviewers have increasingly been hired by the FDA from industry, university research, and the practice of medicine, thus incorporating their experience outside of the government environment and enriching the Agency with sophisticated, experienced, realistic and sound resources. Along with the traditional facilitated approaches to accelerating the medical product review process (e.g., Fast Track, Accelerated Approval, and Orphan Drug Designation), newer programs such as Breakthrough Designation and Regenerative Medicine Advanced Therapy Designation have responded to critical healthcare emergencies and added to the officially sanctioned means for bringing new therapeutic interventions to patients with unmet medical need, while still meeting well-defined standards for safety and efficacy.

We believe that a radical change in the requirements for substantial evidence of both safety and efficacy, if introduced into the FDA, will lead to a massive upheaval in both the morale of Agency Reviewers, and concerns for the overall health of the system for development, review and approval of new diagnostic and therapeutic interventions.

This could also have a significant adverse effect both on the US system for reimbursement and worldwide due to the fallout over the lowered competitiveness of products approved or licensed under inferior standards of risk/benefit. The FDA has often been thought of as a “gold standard” for review of new chemical and biological entities, emulated by regulatory authorities worldwide. Should the US system of substantial evidence of both efficacy and safety imposed prior to marketing approval of new products be compromised, ex-US regulators and reimbursement authorities could well place such products on a second or third tier for accessibility, thus adversely affecting US firms who have developed them under the new legal/regulatory scheme.

The Food, Drug and Cosmetic Act and Public Health Services Act; Must be Changed through new Law in Congress

Last week, we identified a number of areas that would be impacted if there were major changes in how the FDA approved marketing applications.

The first area of impact is the 1962 amendments to the Food, Drug, and Cosmetic Act and the Public Health Service Act. Laws and regulations would need to be changed to result in functional differences in how drugs are evaluated by FDA (an Executive Order can’t do it!)

Congressional approval of one or more laws that would modify or void these Acts is necessary prior to any move to change the FDA review and approval process as well as industry strategies, expenditures and timeframes for moving new products to market.

Some changes could radically alter the risk/benefit profile of drugs and biologicals in the US, with fallout around the world. Nonclinical pharmacology support for clinical trials and the efficacy endpoints for clinical trials themselves could be massively reduced in type and scope, thus leading to uncertainty for patients being treated as well as the healthcare professionals who prescribe the affected products. Although modifications of these requirements could potentially allow for earlier availability of therapeutics to patients, they could also dramatically shift patient exposure to ineffective products, thus sharply reducing their usefulness and cost-benefit and disrupting the financing, resourcing, and eventual success for companies and other Sponsors who discover and develop these products.

The FDA has many programs for accelerated development and patient access to therapeutics that are showing both safety and efficacy potential. These include the treatment IND, single patient compassionate use, emergency IND, EUA, accelerated approval, breakthrough therapy and other designations. These programs have worked well in accelerating the product development process and allowing earlier access to experimental drugs and biologics. A fine-tuning of the system, with evolutionary changes in law, regulation and data requirements, that incrementally impact our entire system of therapeutics is a logical approach to providing access to SAFE AND EFFECTIVE therapies.

The much-anticipated FDA guidelines on the development and review of biosimilars have been recently released, and biologics developers are scrambling to interpret the resulting risks and opportunities. This blog is the first in a series designed to provide orientation on the guidances, and key suggestions for their practical implementation.

The 2009 Biologics Price Competition and Innovation Act allows for the approval of “generic” biologics that are either biosimilar (able to be substituted for innovator products); or biosimilar “interchangeable” (therapeutic alternatives which can be directly substituted for the innovator product without consultation with the healthcare provider). FDA has interpreted this law in three guidances intended to provide aid to sponsors in dealing with the quality, nonclinical and clinical testing issues related to these products; however, there are many unanswered questions for biosimilars developers.

In some ways, the new guidances change nothing. Regulatory decisions on biologics are always based on a weight of evidence/totality of evidence approach. The extensive analytical, physicochemical and biological characterization suggested in the guidance for biosimilar products is the same as that required for new biological entities and in considerations of comparability. FDA is applying their significant experience with changes in the manufacture of originator biologic products (for example, the addition of new manufacturers, processes, and facilities) to hopeful “generic biologics” manufacturers. . FDA acknowledges different risk levels for determinations of biosimilarity, depending on the type of biologic involved, e.g.:

Simple monoclonal antibodies without side chains or conjugates

Recombinant vaccines

Multi-antigen products from expressed sources

Future blogs in this series will address how these FDA sensitivities and perspectives are likely to shape the development of specific classes of new biosimilar products.

The webcast “What You Must Know About FDA’s New Biosimilars Guidance” being presented on April 12, 2012, from 11:00 AM – 12:00 PST will present further information on this topic. You can register for this seminar at http://www.expertbriefings.com/.

Of interest to many drug developers is the October 19 proposed FDA amendment to the Orphan Drug regulations, to address Agency concerns about Sponsor efforts to artificially subset diseases or conditions to obtain the advantages of orphan status during development and after approval.

The revealing preamble to the proposed regulation notes that the existing regulatory language requiring the disease subset to be “medically plausible” has been mistakenly interpreted by Sponsors to mean any medically recognizable or any clinically distinguishable subset of persons with a particular disease or condition.

Sponsors should consider the following practical questions when assessing whether a subset of a non-rare disease or condition is an appropriate orphan subset:

Is the intended subset artificially restricted in any way with respect to the use of the drug to treat the disease or condition?

Given that the drug may potentially benefit this particular subset of persons, is there a reasonable scientific or medical basis for believing that the drug would also potentially benefit the remaining population with the non-rare disease or condition or a larger subset of that population? If not, why not?

An appropriate response to the above questions should be supported by available scientific evidence (e.g. pharmacological or clinical). In two very recent incidents involving GZP clients, we have noted that the FDA is currently acting on the principles included in the proposed regulations, prior to their finalization.